Thiopyranopyrrolylsalicyclic acids and derivatives thereof

ABSTRACT

Thiopyranopyrrolylsalicylic acids and derivatives thereof having the formula   IN WHICH X is hydrogen, hydroxy, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl, nitro, amino, trifluoromethyl or cyano, R is hydroxy, alkoxy of 1 to 6 carbon atoms, amino or hydroxylamino, R1 is hydrogen, alkyl of 1 t 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms, m is 0, 1 or 2 and n is 1, 2 or 3 are disclosed to have useful anti-inflammatory and analgesic activity upon administration to mammals.

United States Patent [191 Allen et a1.

[ Feb. 11, 1975 1 1 TIIIOPYRANOPYRROLYLSALICYCLIC ACIDS AND DERIVATIVES THEREOF [75] Inventors: Richard C. Allen, Somerville, N.J.;

Chandler R. Taylor, Jr., Mechanicsville, Va.

[73] Assignee: American l-Ioechst Corporation,

Bridgewater, NJ.

22 Filed: Mar. 1,1973

21 App1.No.:336,920

[52] US. Cl 260/326.28, 260/327 R, 424/274 [51] Int. Cl C07d 27/54 [58] Field of Search 260/326.28

[56] References Cited OTHER PUBLICATIONS Theilheimer, Synthetic Methods of Organic Chemistry, vol. 6 (1952) No. 401.

Theilheimer, Synthetic Methods of Organic Chemistry, v01. 10 (1956), No. 334.

Primary Examiner.loseph A. Narcavage Attorney, Agent, or FirmCurtis, Morris & Safford [57] ABSTRACT Thiopyranopyrrolylsalicylic acids thereof having the formula and derivatives 13 Claims, N0 Drawings THIOPYRANOPYRROLYLSALICYCLIC ACIDS for reaction in a solvent inert to the reactants and the AND DERIVATIVES THEREOF reaction product, e.g., acetic acid or ethanol, at a temperature between about 20 and 125C. for a period of This invention relates to thiopyranopyrrolylsalicylic from a few minutes to several days. It will readily be apacids and derivatives thereof of the formula 5 preciated by those skilled in the art that the time and temperature necessary to complete the reaction are interrelated and dependent upon the structures and com- 0 I I positions of the reaction components and the solvent.'

I The -diketones em lo ed as'startin materials are l X 1 P y g (ca N prepared by reaction of an appropriate thiocycloalka- TL none enamine with an appropriate phenacyl halide in a solvent such as benzene, toluene or dimethylform- CGR amide (DMF) for a period of from a few minutes to 15 several days at a temperature between 0 and 150C,

0 R the time and temperature necessary to complete the reaction again being interrelated and dependent upon the structures and compositions of the reaction compoin which X is hydrogen, hydroxy, halogen, alkyl of l to nents and the solvent. The preparation of the 'y-dike- 6 carbon atoms, alkoxy of l to 6 carbon atoms, phenyl, 2O tones is illustrated schematically below, X, m and n nitro, amino, trifluoromethyl or cyano, R is hydroxy, being as above and hal being halogen:

O L) h 1 I ff'rz A i r -r. lMT

l J L 7 r l l f 1. F

alkoxy of l to 6 carbon atoms, amino or hydrox- Illustrative examples of the compounds according to ylamino, R is hydrogen, alkyl of l to 6 carbon atoms the present invention are: or alkanoyl of l to 6 carbon atoms, m is 0, 1 or 2 and S-(Z-phenyl-l,4,6,7-tetrahydrothiopyrano[4,3- n is l, 2 or 3, to methods of preparing such compounds, b]pyrroll-yl)salicylic acid; 5-(2-p-fluorophenylto pharmaceutical compositions containing such coml,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrol-lpounds as active anti-inflammatory and analgesic, yl)salicylic acid; 5-(2-m-methoxyphenyl-l,4,6,7- agents, and to a method of treatment therewith. tetrahydrothiopyrano[4,3-b1pyrrol-l-yl)salicylic acid;

To the best of our knowledge, the compounds of this 40 methyl 5-(2-phenyl-l ,4,6,7-tetrahydrothiopyrano[4,3- invention have not heretofore been described. The only b]pyrrol-l-yl)salicylate; 5-(2-o-bromophenyl- 1 ,4,6,7- thiopyrano[4,3-b]pyrrole known to us, l,2,3,7- tetrahydrothiopyrano[4,3-b]pyrrol-l-yl)salicylamide; tetrahydrol -methyl-7,7-diphenyl-4-thiopyrano[4,3- 5-(Z-phenyl-4,6-dihydrothieno[3,4-b1pyrroll b]pyrrole-4,6-dione, described in Angew. Chemie, lnt. yl)salicylic acid; and 2-acetoxy-5-(2phenyl-l,4,6,7- Ed. Engl., Vol. 6, pg, 336 (I967) is outside the scope tetrahydrothiopyrano[4,3-b]pyrrol-1-yl)benzoic acid.

of this invention. The compounds of the present inven- Thiopyrano[4,3-b]pyrrol-l-yl)salicylic acids or de tion are prepared by reaction of an appropriate y-dikerivatives of Formula I, wherein X, R, R and n have the tone with S-aminosalicylic acid or an appropriate derivmeaning as defined above and m is 0, can be oxidized ative thereof according to the reaction scheme to the corresponding sulfoxide or :sulfone of Formula I,

in which X, R, R,, m and n are as defined earlier. In a wherein m is l or 2, respectively. preferred embodiment of the method of this invention, Thiopyrano[4,3-b]pyrrol-l-ylsalicylic acids of Fori the reactants are brought into contact with one another mula I, wherein X, R m and n are defined above and R is hydroxy, can be converted, by standard reactions, to the corresponding esters, amides or hydroxamic acids wherein R is alkoxy of 1 to 6 carbon atoms, amino or hydroxylamino.

Thiopyrano[4,3-b]pyrrol-1-y1)sa1icy1ic acids or derivatives of Formula 1, wherein X, R, m and n have the meaning as defined above and R, is hydrogen can be converted by standard reactions to the corresponding ethers or esters wherein R is alkyl of 1 to 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms.

The preferred compounds of the present invention are thiopyrano[4,3-b]pyrrol-1-y1)sa1icy1ic acids of the formula in which X is as defined earlier. Particularly preferred are those compounds in which X is hydrogen, or Cl, Br, F, CF C11 0 or pheny] substituted in the meta or para position.

The compounds of the present invention are useful as anti-inflammatory agents due to their ability to suppress inflammation in mammals. The activity of the compounds is demonstrated in the carrageenininduced rat paw edema anti-inflammatory assay [Proc. Soc. Exptl. Biol. Med., 111, 544 1962); J. Pharmacol.

Exp. Ther. 141,369 (1963)]. For example, at doses of agent, effects a 53 percent inhibition of-edema at a dose of 128 mg/kg and a 34 percent inhibition of 2- phenyll ,4-benzoquinone-induced writhing at a dose of 60 mg/kg. These data illustrate that the thiopyranopyrrolylsalicylic acids and related compounds of this invention are useful for the suppression of inflammation and pain in mammals when administered in amounts ranging from 1 to about 200 mg per kg of body weight per day.

The compounds of the present invention may be administered by any convenient route such as orally, intramuscularly, intravenously, subcutaneously, or intraperitoneally. The preferred route of administration is oral, for example, with an inert diluent or with an edible carrier or in gelatin capsules or tablets. For the purpose of oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used inthe form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. These preparations should contain at least 0.5 percent of active compound, but may be varied depending upon the particular form and may conve- The tablets, pills, capsules, troches, and the like may also contain the following ingredients: a binder such as gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, potato starch and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or both. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent, and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions must be pharmaceutically pure and non-toxic in the amounts utilized.

The invention is further illustrated by the following examples.

EXAMPLE 1 a. 5,6-Dihydro-4-(1-pyrro1idinyl)-2H-thiopyran;

A solution of 103 g (0.9 mol) of tetrahydrothiopyran- 4-one, g (1.33 mol) of pyrrolidine, and 1 1. of anhydrous benzene was heated under reflux in a nitrogen atmosphere for 2 hrs. until the theoretical amount of water was collected in a water trap. The solvent was distilled and the residue fractionated under reduced pressure to provide 105 g of colorless liquid, b.p. 124C. at 0.01 mm.

b. 3-Phenacyl-2,3,5,6-tetrahydrothiopyran-4-one:

A solution of 56.3 g (0.28 mol) of phenacyl bromide in m1 of DMF was added, in the course of 20 minutes and under a nitrogen atmosphere, to a cooled, stirred solution of 41.6 g (0.28 mol) of 5,6-dihydro-4- (1-pyrrolidinyl)-2H-thiopyran in 300 m1 of anhydrous DMF. After two hours, the solution was diluted with water and extracted with chloroform; the chloroform extracts were washed with water, dried and concentrated. Crystallization from ethanol gave 43 g of solid; mp. 101.5 103.5C.

c. 5-(2-Pheny1-1,4,6,7-tetrahydrothiopyrano[4,3- b]pyrrol-1-y1)salicy1ic acid:

A stirred suspension of 13.7 g (0.06 mol) of 3- phenacyl-2,3,5,6-tetrahydrothiopyran-4-one, 9.0 g (0.06 mol) of S-aminosalicylic acid, and 60 m1 of g1acial acetic acid was refluxed under a nitrogen atmosphere for 1 hours. The reaction mixture was cooled to room temperature and the solid removed by filtration. Recrystallization from acetic acid and acetonitrile 1 yielded 10.4 g (50 percent) of crystals; m.p. 220- 225.5C. (dec.).

Calc. for C H NO S: N;

68.35% C; 4.88% H; Found: 83% H EXAMPLE 2 a. 3-(p-Bromophenacyl)-2,3,5,-tetrahydrothiopyran- 4-one:

A suspension of 41.7 g (0.15 mol) of pbromophenacyl bromide in 50 ml of DMF was added dropwise under nitrogen to a cooled stirred solution of 25.4 g (0.15 mol) of 5,6-dihydro-4-(l-pyrrolidinyl)- 2H-thiopyran in 150 ml of anhydrous DMF. The mixture was stirred at room temperature for 16 hrs., diluted with water and extracted with chloroform. The chloroform solution was dried and concentrated, and the residue was ehromatographed on silica gel with a 1:1 benzene'chloroform mixture as eluent. 24.1 g of a solid was obtained. Recrystallization from ethanol provided 19.8 g. of crystals, m.p. 87.5- 89.5C. b. 5-(2-p-Bromophenyl-1,4,6,7- tetrahydrothiopyrano[4,3-b1-pyrro1-1-yl)salicylic acid:

A stirred suspension of 4.0 g (0.013 mol) of 3-(pbromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one and 1.95 g (0.013 mol) of S-aminosalicylic acid in ml of glacial acetic acid was heated to reflux under nitrogcn for one hour, cooled and filtered to provide 5.2 g (94 percent of crystals. m.p. 260 262C. (dec.).

Calc. for C 11 BrNO S:

55.82% C; 3.75% H; Found: 3 78% H;

EXAMPLE 3 reacted as described in Example 2b for one-half hour,

cooled and filtered to provide 6.6 g (90 percent) of crystals. After recrystallization from ethanol, m.p. 240-243C.(dec.).

Culcfor z., mFN .1S: 65.03% c; 4.37% H; 3.79% N Found: 64.88% C; 4.43% H; 3.67% N EXAMPLE 4 a. 3-(p-Methoxyphenacyl)-2,3,5,6-tetrahydrothiopyran-4-one:

16.9 g (0.1 mol) of 5,6-dihydro-4-(l-pyrrolidinyl)- ZH-thiopyran dissolved in ml. of anhydrous DMF and 23 .2 g (0.1 mol) of a-bromo-pmethoxyacetophenone in 50 ml. of DMF were reacted as described in Example 3a and the reaction mixture was worked up as described in Example la. After crystallization of the crude product from methanol and then from acetic acid, m.p. 123 -125C. b. 5-( Z-p-Methoxyphenyl-l ,4,6,7- tetrahydrothiopyranol4,3-bl-pyrroLl-yl)salicylic acid:

5.0 g (0.02 mol) of 3-(p-methoxyphenacyl)-2,3,5,6- tetrahydrothiopyran-4-one and 2.9 g (0.02 mol) of 50 'aminosalicylic acid in 25 ml. of glacial acetic acid were reacted as described in Example 2b for two hours, the suspension was filtered while hot and the filtrate was cooled and again filtered to provide 6.1 g of solid. After recrystallization from acetonitrile, m.p. 210-212C. (dec.).

Found:

66.12% C; 5.02% H; 3.67% 66.02% C; 5.10% H; 3.99%

EXAMPLE 5 a. 3-(p-Chlorophenacyl)-2,3,5,6-tetrahydrothiopyran- 4-onez 16.9 g (0.1 mol) of 5,6-dihydro-4-(1-pyrro1idinyl)- 2H-thiopyran dissolved in 100 ml. of anhydrous DMF and 23.4 g (0.1 mol) of a-bromo-pchloroacetophenone in 50 ml. of DMF were reacted as described in Example 3a and the reaction mixture was worked up as described in Example 2a. Recrystalli zation from ethanol provided 12.2 g of crystals; m.p. 78 81C. b. 5-(2-p-Chlorophenyl-1 ,4,6,7- tetrahydrothiopyrano[4,3-b]pyrrol-1-yl)salicylic acid:

5.0 g (0.02 mol) of 3-(p-chlorophenacyl)-2,3,5,6- tetrahydrothiopyrano-4-one and 2.9 g (0.02 mol) of 5- aminosalicylic acid in 20 ml. of glacial acetic acid were reacted as described in Example 2b for hrs., cooled and filtered to provide 5 .3 g of crystals. After recrystallization from acetic acid, m.p. 250 253C. (dec.).

Calc. for C H ClNO S: Found:

62.25% C; 4.8% H; 3.63% N; 61.93% C; 4.39% H; 3.51% N.

EXAMPLE 6 mol) of S-aminosalicylic acid in 20 ml. of glacial acetic acid were reacted as described in Example 2b and worked up as described in Example 4b to provide 4.0 g (58 percent) of crystals. After recrystallization from acetonitrile, m.p. 223.5 226C. (dec.).

EXAMPLE 7 a. 3-(m-Methoxyphenacyl)-2,3,5,6-tetrahydrothi0pyran-4-one:

16.9 g (0.1 mol) of 5,6-dihydro-4-(l-pyrrolidinyl)- 2H-thiopyran in 100 ml. of anhydrous DMF and 22.9 g (0.1 mol) of a-bromo-m-methoxyacetophenone in 50 ml. of DMF were reacted as described in Example 3a for three hrs. and the reaction mixture was worked up as described in Example 2a. Recrystallization from ethyl acetate provided 10.8 g of crystals; m.p. 63 -66C.

b. 5-(2-m-Methoxy-1,4,6,7-tetrahydrothiopyrano[4,3- b]pyrrol-1-yl)salicylic acid:

4.0 g (0.015 mol) of 3-(m-methoxyphenacyl-2,3,5,6- tetrahydrothiopyran-4-one and 2.3 g (0.015 mol) of 5- aminosalicylic acid in ml. of glacial acetic acid were reacted as described in Example 2h for three hrs. and filtered. The filtrate were cooled, stirred for one hr. and again filtered. 5.4 g of solids were obtained. After repeated recrystallization from ethyl acetate, pale yellow crystals were obtained; m.p. 214 215.5 (dec.).

Found:

EXAMPLE 8 a. 3-( p-Phenylphenacyl )-2,3 ,5 ,6-tetrahydropyran- 4-one:

4.75 g (0.03 mol) of 5,6-dihydro-4-(l-pyrrolidiny1)- ZH-thiopyran in 30 ml. of anhydrous DMF and 7.7 g (0.03 mol) of a-bromo-p-phenylacetophenone in, 30 ml. of DMF were reacted as described in Example 3a and the reaction mixture was worked up as described in Example 2a to provide 7.2 g of crystals. After recrystallization from methanol and acetic acid, m.p. 142 14 144C.

b. 5-(2-p-Biphenylyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrol-1-y1)salicylic acid:

3.5 g (0.01 mol) of 3-(p-phenylphenacyl)-2,3,5,6- tetrahydropyranl-one, 1.72 g (0.01 mol) of 5- aminosalicylic acid and 15 ml. of glacial acetic acid were heated under reflux under nitrogen for three hours, filtered, cooled and filtered again to provide 3 g of product which was chromatographed on silica gel with a chloroform-methanol mixture and recrystallized from acetonitrile to give 1.5 g of crystals, m.p. 230

Found:

tetrahydrothiopyran-4-one-1,l-dioxide EXAMPLE 9 a. 5,6-Dihydro-4-(1-pyrrolidinyl)-2H-thiopyran-l,1- dioxide:

A mixture of 18.0 g (0.12 mol) of tetrahydrothiopyran-4-one-1,l-dioxide, 13.0 g (0.18 mol) of pyrrolidine, 50 g of 5A molecular sieves, and 400 ml. of anhydrous benzene was shaken for 3.5 hrs. and filtered. The filtrate was concentrated under pressure to a gummy solid.

b. 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one-1,1- dioxide:

23.0 g (0.11 mol) of 5,6-dihydro-4-(1-pyrrolidinyl)- 2H-thiopyran-1,1-dioxide in ml. of anhydrous DMF and 22.8 g (0.11 mol) of phenacyl bromide were reacted as described in Example 3a for 18 hrs. and the reaction mixture was worked up as described in Example 2a, the eluent being a 99:1 benzene-methanol mixture. The crude solid was recrystallized from methanol to give colorless crystals, m.p. 157.5-159C.

c. 5-( 5 ,5-Dioxo-2-phenyl-l ,4,6,7- tetrahydrothiopyrano[4,3-bl-pyrrol-l-yl)salicylic acid:

4.0 g (0.015 mol) of 3-pheacyl-2,3,5,6-

and 2.3 g (0.015 mol) of S-aminosalicylic acid in 15 m1. of glacial acetic acid were reacted as described in Example 2b for 1.5 hrs. and filtered to provide 5.3 g (92 percent) of an off-white solid. Recrystallization from l-butanol gave colorless crystals, m.p. 283C. (dec.).

Found:

EXAMPLE 1O 5-(5-Oxo-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3- b]pyrroll-yl)salicylic acid:

To a cold (0C) stirred solution of 7.5 g (0.02 mol) of 5-(2-phenyl-l ,4,6,7-tetrahydrothiopyrano-[4,3- b]pyrrol-1-yl)salicylic acid (prepared according to Example lc) and 375 ml. of ethanol was added, under nitrogen, a solution of 4.55 g (0.02 mol) of sodium metaperiodate in 100 ml. of water. The mixture was stirred for 18 hrs., diluted with chloroform, and filtered. The layers were separated and the organic phase was washed with water, dried and concentrated to a solid. Two recrystallizations from methanol provided 2.4 g of crystals, m.p. 199 201.5C (dec.).

Calc. for c H Nms; 64.78% C; 4.33% H; 3.73% N; Found: 64.74% C; 4.75% 11:4.1270 N.

We claim: 1. A compound of the formula COR in which X is hydrogemhydroxy, halogenfalkyl of l to 6 carbon atomsyalkoxy of l to 6 carbon atoms, phenyl, nitro, amino, trifluoromethyl or cyano, R is hydroxy, alkoxy of l to 6 carbon atoms or amino, R is hydrogen, alkyl of l to 6 carbon atoms or alkanoyl of l to 6 carbon atoms, and m is 0, l or 2.

2. A compound as defined in claim l of the formula (IOOH l OH wherein X has the meaning defined in claim 1.

3. A compound as defined in claim 2 wherein X is hydrogen, fluoro, chloro, bromo, methoxy, trifluoro methyl or phenyl.

4. The compound defined in claim 3 wherein X is hydrogen.

5. The compound defined in claim 3 wherein X is pbromine.

6. The compound defined in claim 3 wherein x is pfluorine.

7. The compound defined in claim 3 wherein X is pchlorine.

8. The compound defined in claim 3 wherein X is p- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,865,839

DATED February 11, 1975 INVENTOR(S) Allen et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Abstract:

Line 5 after the structural formula, "1 t 6" should read 1 to 6 Column 7, lines 51 to 52, "142 14 144C."

should read 142 144C.

Signed and sealed this 29th day of April 1975.

(SEAL) Attest C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks 

1. A COMPOUND OF THE FORMULA
 2. A compound as defined in claim 1 of the formula
 3. A compound as defined in claim 2 wherein X is hydrogen, fluoro, chloro, bromo, methoxy, trifluoromethyl or phenyl.
 4. The compound defined in claim 3 wherein X is hydrogen.
 5. The compound defined in claim 3 wherein X is p-bromine.
 6. The compound defined in claim 3 wherein X is p-fluorine.
 7. The compound defined in claim 3 wherein X is p-chlorine.
 8. The compound defined in claim 3 wherein X is p-methoxy.
 9. The compound defined in claim 3 wherein X is m-methoxy.
 10. The compound defined in claim 3 wherein X is p-trifluoromethyl.
 11. The compound defined in claim 3 wherein X is p-phenyl.
 12. The compound defined in claim 1 wherein X is hydrogen, R is hydroxy, R1 is hydrogen and m is
 2. 13. The compound defined in claim 1 wherein X is hydrogen, R is hydroxy, R1 is hydrogen and m is
 1. 